EP3341379B1 - Inhibiteurs de l'ezh2 - Google Patents

Inhibiteurs de l'ezh2 Download PDF

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EP3341379B1
EP3341379B1 EP16757513.3A EP16757513A EP3341379B1 EP 3341379 B1 EP3341379 B1 EP 3341379B1 EP 16757513 A EP16757513 A EP 16757513A EP 3341379 B1 EP3341379 B1 EP 3341379B1
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Prior art keywords
methyl
mmol
compound
add
ethyl
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EP3341379A1 (fr
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Esteban DOMINGUEZ
Deqi Guo
Mary Margaret Mader
Anh-Quan Hannah NGUYEN
Miriam Filadelfa Del Prado
Michael Enrico Richett
Michael John Rodriguez
Yvonne Yee Mai Yip
Kuo-Long Yu
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to PL16757513T priority Critical patent/PL3341379T3/pl
Priority to RS20191526A priority patent/RS59615B1/sr
Priority to MEP-2019-322A priority patent/ME03650B/fr
Priority to SI201630453T priority patent/SI3341379T1/sl
Publication of EP3341379A1 publication Critical patent/EP3341379A1/fr
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Priority to HRP20192101TT priority patent/HRP20192101T1/hr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that inhibit activity of the histone lysine methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, such as hematologic and solid tumors.
  • EZH2 Enhancer of Zeste Homolog 2
  • EZH2 is encoded by the EZH2 gene, and is the catalytic component within polycomb repressive complex 2 (PRC2) that is responsible for the methylation of lysine 27 on histone 3 (H3K27) on chromatin.
  • PRC2 polycomb repressive complex 2
  • EZH2 overexpression is thought to promote cancer as a result of increases in histone methylation which silences the expression of tumor suppressor genes.
  • the catalytic activity of EZH2 is mediated by a 130 amino acid Su(var)3-9, enhancer of Zeste and trithorax (SET) domain, which provides the binding pockets for S-adenosylmethionine (SAM) cofactor and the lysine substrate residue.
  • SAM S-adenosylmethionine
  • the core PRC2 complex is comprised of EZH2 and proteins EED (Embryonic Ectoderm Development), SUZ12 (Suppressor of Zeste 12 homolog) and RbAp46/48 (also known as RBBP7/4), and can also include other proteins such as JARID2, AEBP2, and Polycomblike (PCL) 1/2/3.
  • H3K27 methylation can also arise due to mutations which increase the catalytic efficiency of EZH2, such as Y641N, A677G, and A678V.
  • levels of H3K27 methylation can be modulated in solid tumors through various signaling pathways, such as those involving VEGFR2 and PI3K/AKT.
  • SWI/SNF and PRC2 complexes play antagonistic roles in the activation and repression of transcription, respectively.
  • Tumors that lack or are defective in SWI/SNF protein SNF5 can demonstrate aberrant methylation and repression by PRC2 and are growth-inhibited following treatment with EZH2 small molecule inhibitors.
  • SWI/SNF protein ARID1A also known as BAF250
  • constitutively activating mutations in components of the PI3K pathway such as PIK3CA
  • EZH2 small molecule inhibitors are also growth-inhibited following treatment with EZH2 small molecule inhibitors.
  • tumors that lack or are defective in both SMARCA2 (also known as BRM) and SMARCA4 are also growth-inhibited following treatment with EZH2 small molecule inhibitors.
  • H3K4 methyltransferase also known as MLL or COMPASS
  • H3K4 methyltransferase also known as MLL or COMPASS
  • Tumors that lack or are defective in H3K4 methyltransferase complex components including but not limited to MLL2 (data shown herein for combination treatment with an EZH2 inhibitor plus Standard of Care chemotherapy in patient-derived xenograft models of gastric cancer), MLL3 (data shown herein for combination treatment with an EZH2 inhibitor plus Standard of Care chemotherapy in patient-derived xenograft models of lung cancer), Lysine-specific demethylase 6A, also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX, also known as KDM6A [ Ezponda, T. et al.
  • EZH2 inhibitors are already known in the literature. See for example, WO2012/142504 , WO2012/142513 , WO2013/120104 , WO2013/173441 , WO2013/075083 , WO2014/177982 , WO2014/097041 , and WO2016/066697 .
  • the present invention provides certain inhibitors of EZH2 which may be useful for treating cancer.
  • the present invention provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention also provides a compound of the formula: wherein:
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound which is or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or salt thereof of the present invention and one or more pharmaceutically acceptable excipients, carriers, or diluents.
  • This invention also provides a compound or salt thereof of the present invention for use in therapy. Additionally, this invention provides a compound or salt thereof of the present invention for use in the treatment of cancer wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/SNF complex (for instance, SNF5), MLL complexes, and constitutively active PI3K pathway, sarcomas, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer.
  • the cancer is diffuse large B-cell lymphoma or follicular lymphoma.
  • the cancer is diffuse large B-cell lymphoma.
  • the cancer is gastric cancer.
  • the cancer is ovarian cancer.
  • the cancer is multiple myeloma.
  • the cancer is lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is a solid or hematological tumor that bears wild type (WT) EZH2 as well as a solid or hematological tumor that bears mutant EZH2.
  • WT EZH2 wild type
  • the cancer is a solid or hematological tumor that bears mutant EZH2.
  • the cancer is a solid or hematological tumor that bears WT EZH2.
  • the cancer is a solid or hematological tumor that bears mutant EZH2.
  • a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with carboplatin and paclitaxel in the treatment of ovarian cancer.
  • a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with oxaliplatin and paclitaxel in the treatment of gastric cancer.
  • a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with gemcitabine and cisplatin in the treatment of lung cancer.
  • a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with irinotecan and oxaliplatin in the treatment of colorectal cancer.
  • trans- is as depicted below wherein substituents at the 1,4 positions around the cyclohexyl moiety are trans- relative to one another: wherein R is selected from among dimethylamino, N-methyl-N-methoxyethylamino, N-cyclopropyl-N-methylamino, or azetidin-1-yl, optionally substituted with methoxy, ethoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N -triazolyl, pyrrolidin-4-yl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl and X and Y are as previously defined.
  • a compound of the present invention is capable of forming salts.
  • the compound of the present invention is a base, and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable salts.
  • Such pharmaceutically acceptable acid addition salts and common methodology for preparing them are well known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008 ); S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977 .
  • a compound or salt thereof of the present invention may be prepared by a variety of procedures known in the art, some of which are illustrated in the Preparations and Examples below.
  • the specific synthetic steps described may be combined in different ways to prepare compounds or salts of the present invention.
  • the products of the synthetic steps can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • the reagents and starting materials are readily available to one of ordinary skill in the art.
  • Some intermediates or compounds of the present invention may have one or more chiral centers.
  • the present invention contemplates all individual enantiomers or diastereomers, as well as mixtures of the enantiomers and diastereomers of said compounds including racemates. It is preferred that compounds of the present invention containing at least one chiral center exist as single enantiomers or diastereomers.
  • the single enantiomers or diastereomers may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomers or diastereomers may be isolated from mixtures by standard chiral chromatographic or crystallization techniques. The skilled artisan will appreciate that in some circumstances the elution order of enantiomers or diastereomers may be different due to different chromatographic columns and mobile phases.
  • variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed.
  • the protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example " Greene's Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007 ).
  • CDI carbonyldiimidazole
  • CO 2 carbon dioxide
  • CV column volume
  • Ci Curie
  • CPM counts per million
  • CPr cyclopropyl
  • DCE 1,2-dichloroethane
  • DCM methylene chloride or dichloromethane
  • DIBAL-H diisobutyl aluminum hydride
  • DIPEA diisopropylethyl amine
  • dm refers to decimeters or 10 centimeters
  • DMA refers to dimethylacetamide
  • DMEA N,N-dimethylethylamine
  • DMF dimethylformamide or N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • DNase refers to de
  • the R - or S - configuration of the compounds of the invention may be determined by standard techniques such as X-ray analysis. 1 H NMR, chiral HPLC, and correlation with chiral-HPLC retention time may be used to further elucidate stereoisomerism if one center is known.
  • LC-ES/MS is performed on an Agilent HP1100 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to the HP1100 HPLC.
  • LC-MS conditions low pH: column: Phenomenex GEMINI® NX C-18 2.1 ⁇ 50 mm 3.0 ⁇ m; gradient: 5-100% B in 3 min, then 100% B for 0.75 min column temperature: 50 °C +/-10 °C; flow rate: 1.2 mL/min; Solvent A: deionized water with 0.1% HCOOH; Solvent B: ACN with 0.1% formic acid; wavelength 214 nm.
  • Preparative reversed phase chromatography is performed on an Agilent 1200 LC-ES/MS equipped with a Mass Selective Detector mass spectrometer and a Leap autosampler/fraction collector. High pH methods are run on a 75 X 30 mm Phenomenex GEMINI®-NX, 5 ⁇ m particle size column with a 10 X 20 mm guard. Flow rate of 85 mL/min. Eluent is 10 mM ammonium bicarbonate (pH 10) in ACN.
  • NMR spectra are performed on a Bruker AVIII HD 400 MHz NMR Spectrometer, obtained as CDCl 3 or (CD 3 ) 2 SO solutions reported in ppm, using residual solvent [CDCl 3 , 7.26 ppm; (CD 3 ) 2 SO, 2.50 ppm] as a reference standard.
  • peak multiplicities the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broad singlet), dd (doublet of doublets), dt (doublet of triplets).
  • Coupling constants (J) when reported, are reported in hertz (Hz).
  • Scheme 1 illustrates the formation of a substituted 1,4-dioxaspiro[4,5]decane (compound 5) starting from a protected 4-oxocyclohexanecarboxylate (compound 1).
  • the protected 4-oxocyclohexanecarboxylate may be treated with p-toluenesulfonic acid, triethyl orthoformate and ethylene glycol in a solvent such as EtOH to give the protected 1,4-dioxaspiro[4,5]decane-8-carboxylic ester which may then be deprotected by procedures well known in the art, such as by using an aqueous base, to give 1,4-dioxaspiro[4,5]decane-8-carboxylic acid over 2 steps (compound 2, Scheme 1, Step A).
  • the Weinreb amide (compound 3) may be prepared from the acid product of Step A with the addition of a coupling reagent such as CDI or HOBt in small portions followed by the addition of N-methoxymethanamine hydrochloride in small portions (Scheme 1, Step B).
  • the Weinreb amide (compound 3) may be converted to the ketone (compound 4) using an organometallic reagent such as a Grignard reagent or an organolithium reagent (Scheme 1, Step C). More specifically, methyl magnesium bromide may be added in an appropriate solvent such as Et 2 O and/or THF to give the methyl ketone (compound 4).
  • the methyl ketone (compound 4) may be converted to the vinyl phosphonate (compound 5) with drop wise addition of a non-nucleophilic base such as LiHMDS in a solvent such as THF with the addition of diphenyl phosphorochloridate (Scheme 1, Step D).
  • a non-nucleophilic base such as LiHMDS
  • THF solvent
  • diphenyl phosphorochloridate diphenyl phosphorochloridate
  • a palladium (II) source in the presence of a dibasic ligand such as 1,10-phenanthroline in the presence of a non-nucleophilic base such as DIPEA or TEA using an unsymmetrical vinyl ether as the solvent.
  • the vinyl group may be converted to the protected 3-cyclopropoxyazetidine (compound 8) by a Simmons-Smith reaction or similar carbene-generating conditions, for example, using chloroiodomethane and an alkylzinc reagent in DCE, as shown in Scheme 2, Step B.
  • Deprotection of the protected 3-cyclopropoxyazetidine (compound 8) under standard conditions as those well described in the art, followed by treatment of the free base with a solution of mineral acid in organic solvent, such as HCl in diethyl ether or 1,4-dioxane, may provide the stable azetidine salt (compound 9a).
  • substituted azetidines may be prepared from the commercially available benzhydrylazetidine mesylate (compound 10) by treatment with a wide variety of N, O, C and S containing nucleophiles under nucleophilic substitution conditions using an appropriate base such NaHCO 3 , K 2 CO 3 , DIPEA or TEA and microwave heating, or by treatment with a strong base such as NaH, KOtBu or LHMDS and heating in a polar organic solvent such as DMF or DMSO, to give a substituted benzhydrylazetidine (compound 11, Scheme 3, Step A). Subsequent deprotection under catalytic hydrogenation (Scheme 3, Step B) may yield the desired substituted azetidine (compound 12).
  • an appropriate base such NaHCO 3 , K 2 CO 3 , DIPEA or TEA and microwave heating
  • a strong base such as NaH, KOtBu or LHMDS
  • a polar organic solvent such as DMF or DMSO
  • Scheme 4 depicts the preparation of 2-alkoxy-3-chloromethyl-4,6-dimethylpyridines (compound 17, where R a is CH 3 ,CH 2 CH 3 , or Bn), which may be prepared starting from commercially available 3-cyano-4,6-dimethylpyridone (compound 13). Alkylation of the 3-cyano-4,6-dimethylpyridone (compound 13) with the appropriate alkyl halide under standard literature conditions known to one skilled in the art, may provide the desired 2-alkoxy-3-cyano-4,6-dimethylpyridine (compound 14).
  • Scheme 5 illustrates the synthesis of methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carboxylate (compound 20).
  • the aryl bromide (compound 18) may be carbonylated using an array of palladium(II) catalysts and a variety of appropriate phosphine ligands, specifically palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene, in the presence of an alcohol such as MeOH in a polar solvent such as DMF or DMA with or without a non-nucleophilic organic base such as DIPEA or TEA, under a pressurized atmosphere of carbon monoxide, to obtain the ester (compound 19, Scheme 5, Step A).
  • borolane esterification may be effected either by deprotonation with an alkyl metallating reagent such as n -butyl-, s -butyl-, or t -butyllithium with quenching of the aryl anion with a borate ester, or by transition-metal coordination complexes using palladium(II), iridium(I), or iron(III), to obtain the desired boronic ester.
  • an alkyl metallating reagent such as n -butyl-, s -butyl-, or t -butyllithium with quenching of the aryl anion with a borate ester
  • transition-metal coordination complexes using palladium(II), iridium(I), or iron(III
  • ester (compound 19) may be treated with bis(1,5-cyclooctadiene)di- ⁇ -methoxydiiridium(I) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane portion wise in a nonpolar solvent such as cyclohexane with concomitant heating to obtain methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carboxylate (compound 20, Scheme 5, Step B).
  • a nonpolar solvent such as cyclohexane
  • the 2-ethoxypyridine (compound 27) may be prepared according to the route depicted in Scheme 6, starting with condensation of malononitrile with acetyl ketene under basic conditions in an appropriate polar organic solvent, such as sodium hydride and THF, to obtain the 2-amino-3-cyanopyranone (compound 21, Scheme 6, Step A). Subsequent thermal rearrangement with an inorganic acid, such as HCl, may give the 3-cyano-4-hydroxy-6-methylpyridone (compound 22, Scheme 6, Step B).
  • Chlorination to the 4-chloropyridone may be effected using many chlorinating agents well known in the art, more specifically a mixture of POCl 3 and PCl 5 (Scheme 6, Step C); alkylation of the resulting pyridone (compound 23) may be achieved via metal-mediated etherification with an alkyl halide in an appropriate non-polar organic solvent, more specifically using silver(I) oxide and iodoethane in toluene, to give the 2-ethoxy-3-cyano-4-chloropyridine (compound 24, Scheme 6, Step D).
  • Scheme 7 depicts the synthesis of compounds of Formula I.
  • Coupling of the prepared vinyl phosphate (compound 5, Scheme 1, Step D) with the aryl boronate ester (compound 20, Scheme 5, Step B) under standard Suzuki-type coupling conditions utilizing a palladium(II) catalyst and a phosphine ligand with a mild inorganic base such as K 3 PO 4 in a polar organic solvent such as 1,4-dioxane may give the vinyl thiophene ester (compound 28, Scheme 7, Step A).
  • Reduction of the vinyl moiety may be accomplished by procedures well documented in the art to obtain the ⁇ -methyl thiophene ester (compound 29, Scheme 7, Step B).
  • Stereoselective reduction of the vinyl group may be achieved using an array of catalysts and ligands well documented in the art, especially with an iridium(I) catalyst/ligand complex such as [(4R,5R)-(+)-O-[1-benzyl-1-(5-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl] (dicyclohexylphosphinite) (1,5-COD) iridium(I) tetrakis (3,5-bis(trifluoromethyl)phenylborate to yield the desired stereospecific ester (compound 29).
  • an iridium(I) catalyst/ligand complex such as [(4R,5R)-(+)-O-[1-benzyl-1-(5-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl] (dicyclohexylphosphinite)
  • Subsequent bromination in Scheme 7, Step C, to give the 5-bromothiophene ester (compound 30), may be effected using a brominating agent such as elemental bromine or NBS in a suitable organic solvent such as CHCl 3 , DCM, EtOAc, 1,4-dioxane or CCl 4 .
  • a brominating agent such as elemental bromine or NBS in a suitable organic solvent such as CHCl 3 , DCM, EtOAc, 1,4-dioxane or CCl 4 .
  • Reductive amination may be effected in the presence of a Lewis acid such as titanium isopropoxide and a reducing agent such as NaBH 4 , Na(OAc 3 )BH, or NaCNBH 3 in a suitable solvent such as DCM or MeOH, to obtain a mixture of the trans- and-cis- cyclohexane (compound 34, Scheme 7, Step G), which may be separable by crystallization or chromatography methods well known in the art. Further, one skilled in the art may recognize that utilization of LiBH 4 as a reducing agent may lead primarily to the trans-stereoisomer.
  • the carbobenzyloxy amine (compound 31, Scheme 7, Step D) may be subjected to hydrogenolysis using conditions well known in the art, for example with Pd(OH) 2 on carbon in a suitable organic solvent such as MeOH, and hydrogenolysis may be effected in the presence of a pyridine aldehyde (e.g., compound 15, Scheme 4, Step B), to give methyl 5-[1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl]-4-methyl-2-[2-[(6-methyl-3-pyridyl)methylamino]ethyl]thiophene-3-carboxylate (compound 35, Scheme 7, Step I). Subsequent unmasking to the ketone, reductive amination, cyclization under thermal acidic conditions, and O-deprotection as above may yield the compounds of Formula I (Scheme 7, Steps J-M).
  • a pyridine aldehyde e.g., compound 15,
  • Scheme 8 depicts the synthesis of compounds of Formula II. Nitration of the ester (compound 19, Scheme 5, Step A) with subsequent nitro reduction under standard conditions may yield methyl 5-amino-4-methyl-thiophene-3-carboxylate (compound 40, Scheme 8, Steps A-B).
  • a cyclohexanone such as 1,4-dioxaspiro[4.5]decan-8-one
  • a suitable organic solvent such as DCE
  • the ketal (compound 45, Scheme 8, Step G) may first be dealkylated to obtain the pyridone ketone(compound 48, Scheme 8, Step K) under similar conditions described in Scheme 7. Subsequent alkylation followed by reductive amination or double reductive amination (under conditions similar to Scheme 8, Step C) may be performed to obtain the compounds of Formula II (Scheme 8, Step L)
  • Scheme 9 depicts the synthesis of compounds of Formula III.
  • An N-alkylated methyl 2-bromo-5-[R 5 -(1,4-dioxaspiro[4.5]decan-8-yl)amino]-4-methyl-thiophene-3-carboxylate (compound 42, Scheme 8, Step D) may be alkynylated via transition-metal mediated coupling procedures well known in the art.
  • the bromothiophene (compound 42) may be treated with benzyl prop-2-yn-1-yl carbamate in the presence of CuI, an appropriate palladium(II)-ligand complex, such as bis(triphenylphosphine)palladium(II) dichloride, and a non-nucleophilic organic base such as TEA, to obtain the alkyne (compound 49, Scheme 9, Step A). Subsequent reduction of the alkyne and deprotection of the amine moiety is well known in the art.
  • Scheme 10 depicts the synthesis of compounds of Formula IV starting with the appropriately substituted 5-bromothiophene ester (compound 30), utilizing methods similar to those described in Scheme 9 (Scheme 10, Steps A-F).
  • 3,4-dimethylthiophen-2-amine (compound 40) may be treated with tert-butyl-4-oxopiperidine-1-carboxylate in an appropriate organic solvent such as DCE with portion wise addition of a suitable reducing agent such as Na(OAc) 3 BH with subsequent addition of formaldehyde or acetaldehyde to obtain the N-alkylated N-piperidinyl thiophene (compound 59).
  • a suitable reducing agent such as Na(OAc) 3 BH
  • Scheme 12 shows the synthesis of compounds of Formula VI.
  • Double alkylation of the aminothiophene (compound 40) under reductive amination conditions specifically using first an appropriately protected 4-aminocyclohexanone and then acetaldehyde in the presence of Na(OAc) 3 BH, may give the N-alkylated thienylcyclohexylamine (compound 64, Scheme 12, Step A).
  • N-methylation to this N-alkylated thienylcyclohexyl amine may be effected by first protecting the amino thiophene with an appropriate amine protecting group, such as BOC, followed by treatment of the subsequent carbamate with a strong base, such as NaH or KOtBu, treatment of the resulting anion with an alkyl halide such as CH 3 I, removal of the amine protecting group, and finally reductive amination with an appropriately protected 4-aminocyclohexanone.
  • an appropriate amine protecting group such as BOC
  • a strong base such as NaH or KOtBu
  • an alkyl halide such as CH 3 I
  • Scheme 13 depicts an alternative synthesis of compounds of Formula II. Unmasking the ketal (compound 42, Scheme 8, Step D) under acidic conditions similar to those described in Scheme 7, Step J or Scheme 8, Step K, may give the corresponding ketone (compound 73, Scheme 13, Step A). Double reductive amination under conditions similar to Scheme 8, Step L, may result in the cyclohexylamine (compound 74, Scheme 13, Step B), and subsequent transition-metal mediated coupling under conditions described in Scheme 7, Step D, followed by amine deprotection well described in the literature, may give aminocyclohexane (compound 75, Scheme 13, Step C).
  • Scheme 14 illustrates an alternative synthetic pathway to compounds of Formula IV.
  • the alkyne compound 54 (Scheme 10, step A) may be simultaneously reduced and deprotected using an array of techniques well known in the art, such as catalytic hydrogenation with palladium(II) hydroxide, and in situ reductive amination with an appropriately substituted 2-alkoxypyridine, such as 4,6-dimethyl-2-alkoxypyridine, may be accomplished under conditions similar to those depicted in Scheme 9, step B to give ketal compound 78.
  • Methyl 5-[(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl]-4-methylthiophene-3-carboxylate hydrochloride may be prepared essentially as described in Preparation 40a, with solvent evaporation of the crude reaction mixture following HCl quenching, and chromatography on silica, eluting with a gradient of 0-100% 2M NH 3 /MeOH in DCM, to give oil after solvent evaporation, which partially crystallized upon drying in vacuo. Subsequent recrystallization from EtOAc and a trace of MeOH gives crystalline material sufficient for X-ray crystallography. ES/MS (m/z): 352 (M+H).
  • Refine the absolute structure parameter is to 0.081(12). Determine the structure.
  • the structure is determined to be the hydrochloride salt and absolute structure is determined to be R- configuration at the stereocenter and trans-configuration around the cyclohexane ring.
  • Example No. 1 Prepare the following compounds essentially by the method of Example 2 utilizing the appropriate 5-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-2-[(1R)-1-[4-substituted-cyclohexyl]ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4-one and purifying by either normal- or reverse-phase chromatography.
  • Example 17 5-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-[(1R)- ⁇ trans-4-[3-(2-methoxyethoxy)azetidin-1-yl]cyclohexyl ⁇ ethyl)]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H) -one
  • Example 18 5-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-[(1R)- ⁇ cis-4-[3-(2-methoxyethoxy)azetidin-1-yl]cyclohexyl ⁇ ethyl)]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H) -one
  • Example 25 5-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-(ethyl ⁇ cis-4-[3-(1H-pyrazol-1-yl)azetidin-1-yl]cyclohexyl ⁇ amino)-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H) -one
  • reaction mixture Cool the reaction mixture to -78 °C and then add 2 M lithium borohydride in THF (1.0 mL, 2.0 mmol). After 3 hr, remove the cold bath and stir for 1 hr at RT. Pour the reaction mixture into an ice-cold saturated aqueous NaHCO 3 solution and concentrate in vacuo. Subject the resulting residue to reverse phase chromatography eluting with a gradient of 0-50% ACN (containing 0.1% formic acid) in water (containing 0.1% formic acid). Collect the pure fractions and concentrate to afford the product as the formic acid salt. Combine the product with material from a previously run reaction of about 2 times the scale following a similar procedure.
  • EZH2 expression has been linked in the literature to multiple types of cancer, for example, lymphomas ( Velichutina, I. et al. (2010) Blood 116:5247-55 ; Sneeringer, C.J. et al. (2010) Proc Natl Acad Sci USA. 107:20980-5 ; McCabe et al. (2012) Nature 492:108-12 . Béguelin, W. et al. (2013) Cancer Cell 23:677-92 ; Knutson, S.K. et al. Mol Cancer Ther 13:842-54 ), rhabdoid tumors ( Knutson, S.K. et al. (2013) Proc Natl Acad Sci U S A.
  • IC 50 refers to the concentration of an agent which produces 50% of the maximal inhibitory response possible for that agent, (relative IC 50 ), or the concentration of an agent which produces 50% inhibition of the target enzyme activity compared to placebo control (absolute IC 50 ).
  • This assay is to measure the compound effect on the catalytic activity of EZH2 WT/Y641N in the context of the PRC2 complex.
  • test compounds in 100% DMSO 50 ⁇ L of a 4 mM stock for WT assay or 50 ⁇ L of a 0.2 mM stock for mut assay
  • DMSO 50% DMSO
  • a 384 well NUNCTM plate Place 20 ⁇ L 100% DMSO in dilution wells. Perform 3 ⁇ serial dilutions by transferring 10 ⁇ L from one well to the next.
  • Final assay conditions are 2.5 nM enzyme complex, 10 nM tri-methyl histone /co-activator H3 peptide, 1 ⁇ M biotin substrate peptide, 1 ⁇ M 3 H-SAM, and test compound at a top concentration of 1 ⁇ M (WT assay); or 5 nM enzyme complex, 0.5 ⁇ M biotin substrate peptide, 0.5 ⁇ M 3 H-SAM, and test compound at a top concentration of 1 ⁇ M (mut assay).
  • Reconstitute Yttrium Silicate Streptavidin SPA beads Perkin Elmer, Cat# RPNQ0012
  • the compounds of Examples 1 and 20 have biochemical IC 50 results that demonstrate inhibition of the methyltransferase activity of recombinant WT/mut EZH2 in the context of the PRC2 complex.
  • This assay is to evaluate the ability of a compound to inhibit the functional activity of EZH2 in cells, via measurement of levels of cell tri-methylated H3K27.
  • Plate Karpas-422 (EZH2 Y641N) cells at 5,000 cells/100 ⁇ L/well in black 96-well BD BIOCOAT® Cellware, Poly-Lysine plates (BD Biosciences, Cat# 354640).
  • Example 1 Cover plates with black plate seals and scan on ACUMEN® laser scanning cytometer (TTP Lab Tech) with Ex 488nm/Em 505 nm-530 nm (H3K27m3 signal) and LP655nm (cell nuclear signal).
  • Compounds within the scope of the invention may be tested in this assay substantially as described above.
  • the purpose of this assay is to demonstrate the ability for test compounds to inhibit the growth of tumor cells in vitro.
  • This assay is to evaluate the ability of a test compound to inhibit tumor EZH2 function and EZH2-mediated tumor growth in vivo.
  • RNASE/DNASE-free tubes with beads for homogenization (MP Biomedicals, Cat# 6913-500).
  • MSD Blocking Solution A (Meso Scale Discovery (MSD); final concentration of 3%) to a MULTI-SPOT® Tri-Methyl-Histone H3(K27) SINGLEPLEX® plate (MSD; Cat#: N45CA-1). Shake at RT for 1 hr. Wash the plate with IX MSD Tris Wash BufferTM (MSD), (3 ⁇ ). Dispense 0.25 ⁇ g of tumor lysate in 25 ⁇ L Acid Lysis Buffer per well in triplicate. Shake overnight at 4 °C. Wash the plate three times with IX MSD Tris Wash BufferTM.
  • RNASE/DNASE-free tubes with beads for homogenization (MP Biomedicals, REF: 6913-500).
  • EZH2 inhibitors including but not exclusive to Ex. 1 or Ex. 38, alone and/or in combination with Standard of Care (SoC) chemotherapy, in the treatment of ovarian, gastric, lung or colorectal cancers bearing combinations of mutations in components of the SWI/SNF complex and/or MLL complex and/or PI3K pathway.
  • SoC Standard of Care
  • ovarian cancers lacking ARID1A protein expression combined with mutations in PTEN or PIK3CA and/or constitutive protein expression of Akt phosphorylated on threonine 308 (Thr308).
  • Thr308 Akt phosphorylated on threonine 308
  • these include but are not exclusive to ovarian cancers lacking both SMARCA2 and SMARCA4 protein expression.
  • these include but not are not exclusive to gastric cancers bearing heterozygous loss of function (LOF) mutations (including but not limited to nonsense, frameshift and coding-splice mutations) in ARID1A combined with heterozygous LOF mutations in MLL2, and which do not bear homozygous mutations in TP53. Additionally, these include but are not exclusive to gastric cancers bearing a heterozygous LOF mutation (including but not limited to nonsense, frameshift and coding-splice mutations) in ARID1A combined with a mutation in PTEN or PIK3CA and/or constitutive protein expression of Akt phosphorylated on Thr308, and which do not bear a homozygous mutation in TP53.
  • LEF loss of function
  • these include but are not exclusive to lung cancers with heterozygous LOF mutations in MLL3. Additionally, these include but are not exclusive to colorectal cancers with heterozygous LOF mutations in ARID1A combined with mutations with mutations in PTEN or PIK3CA and/or constitutive protein expression of Akt phosphorylated on Thr308.
  • BD BioSciences BD BIOCOATTM Cellware, Poly-Lysine, Cat. #354640
  • #G7570 as follows: 1) Thaw the CELLTITER-GLO® buffer and equilibrate to room temperature; 2) Equilibrate the lyophilized CELLTITER-GLO® substrate to room temperature; 3) Transfer CELLTITER-GLO® buffer to substrate bottle to form the CELLTITER-GLO® reagent; 4) Equilibrate cell plates to room temperature; 5) For adherent cells only - remove medium from cell plates; 6) Add 25 ⁇ L CELLTITER-GLO® reagent to each well; 7) Let plates incubate an additional 20-30 min at room temperature; 8) Read luminescence using the Perkin Elmer EnVision 2104 Multi Detection Microplate Reader.
  • Table 1 summarizes the effect of Example 38 on a panel of ovarian cell lines and show sensitivity to EZH2 inhibitors in ovarian cancer cell lines that are either both AR1D1A-negative and phosphorylated on Thr308 on Akt, or lack expression in both SMARCA2 and SMARCA4.
  • Table 1 summarizes the effect of Example 38 on a panel of ovarian cell lines and show sensitivity to EZH2 inhibitors in ovarian cancer cell lines that are either both AR1D1A-negative and phosphorylated on Thr308 on Akt, or lack expression in both SMARCA2 and SMARCA4.
  • Table 1 summarizes the effect of Example 38 on a panel of ovarian cell lines and show sensitivity to EZH2 inhibitors in ovarian cancer cell lines that are either both AR1D1A-negative and phosphorylated on Thr308 on Akt, or lack expression in both SMARCA2 and SMARCA4.
  • Table 1 summarizes the effect of Example 38 on a panel of ovarian cell lines and
  • Example 38 compared to ovarian cancer SoC carboplatin plus paclitaxel is tested in vivo using an A2780 xenograft model.
  • Formulate carboplatin (APP Pharmaceuticals NDC 63323-172-60) in phosphate buffered saline (PBS) and administer at 60 mpk very 2 weeks (Q14D) by intraperitoneal (i.p.) injection.
  • Formulate paclitaxel Hospira, Inc NDC 61703-342-50
  • IV intravenous
  • Example 38 Effect of Example 38, ovarian SoC carboplatin plus paclitaxel, and Example 38 in combination with SoC on A2780 tumor growth, on dosing day 28.
  • START Discovery http://startdiscovery.net/ has a platform of patient-derived tumor models. Select two START Discovery ovarian patient-derived models based on presence or absence of SWI/SNF component loss-of-function and PI3K pathway mutations, and test at START Discovery for the effect of Example 1 on tumor growth. Treat 2 groups of 2 mice each for 28 days. Treat Group 1 with ovarian Standard of Care (SoC) compounds carboplatin (formulated in 0.9% NaCl and administered at 60 mpk Q14D i.p.) and paclitaxel (formulated in 0.9% NaCl and administered at 10 mpk Q14D IV).
  • SoC ovarian Standard of Care
  • Pretreat group 2 with Example 1 (formulated in 1% HEC/0.25% TWEEN® 80/0.05% Antifoam and administered at 50 mpk BID p.o.) for 5 days, followed by co-administration with Example 1 and SoC for 23 days or until tumor volumes reach 2000 mm 3 .
  • Table 3 summarizes the effect of Example 1 treatment on the growth of the two patient-derived ovarian tumor models.
  • ST884 - a patient derived ovarian tumor model showing significant tumor growth inhibition with Example 1 treatment bears a homozygous mutation in ARID1A combined with a mutation in PIK3CA.
  • ST416 - a patient derived ovarian tumor model which is heterozygous mutant ARID1A and no mutation in PIK3CA or PTEN - does not show tumor growth inhibition with Example 1 treatment.
  • Table 3 Effect of ovarian cancer Standard of Care (SoC) carboplatin and paclitaxel, or the combination of Example 1 plus SoC, on the growth of 2 ovarian patient derived tumor models.
  • SoC Standard of Care
  • Oncotest (http://www.oncotest.com/) also has an established large collection of patient tumor explants transplanted directly from patients and passaged subcutaneously in nude mice as PDXs. Select 9 Oncotest gastric PDXs based on the presence of loss-of-function (LOF) SWI/SNF and/or MLL complex mutations, and test at Oncotest for effect of Example 1 or vehicle on tumor growth.
  • LEF loss-of-function
  • Example 1 Example 1 or vehicle on tumor growth.
  • Monitor models showing tumor stasis or regression at day 28 post dose cessation until tumor re-growth is observed.
  • Oncotest gastric PDXs treat 2 groups of 2 mice each for 28 days. Treat group 1 with gastric Standard of Care (SoC) compounds oxaliplatin (formulated in 5% glucose and administered at 8 mpk Q14D i.p.) and paclitaxel (formulated in 0.9% NaCl and administered at 10 mpk Q14D IV). Pretreat group 2 animals with Example 1 (formulated in 1% HEC/0.25% TWEEN® 80/0.05% Antifoam and administered at 50 mpk BID p.o.) for 5 days, followed by co-administration with Example 1 and SoC for 23 days or until tumor volumes reach 2000 mm 3 . Calculate the average % change in tumor volume as the mean of individual animal [(tumor volume at treatment day ⁇ 28 minus tumor volume at day 0), divided by tumor volume at day 0], multiplied by 100.
  • SoC gastric Standard of Care
  • Table 4 summarizes the results of the effects of Example 1 treatment on the growth of the patient-derived gastric cancer models (carcinomas or adenocarcinomas), and show that models whose growth is impeded with Example 1 treatment bear two mutations: 1) at least one heterozygous LOF mutation in ARID1A and 2) either a heterozygous LOF in MLL2 (found in PDXs GXA-3052, GXA-3079, GXA-3083) and/or a mutation affecting components of the PI3K pathway (including but not limited to PIK3CA and PTEN; found in PDXs GXA-3002 and GXA-3005).
  • Models whose growth is not inhibited following Example 1 treatment have a homozygous mutation in p53, regardless of LOF mutation status in ARID1A or MLL2 (as in PDX GXA 3011), and regardless of mutation status of the components of the PI3K pathway (as in PDX GXA-3069).
  • Table 4 Effect of SoC oxaliplatin plus paclitaxel, or the combination of Example 1 plus SoC, on the growth of patient-derived gastric cancer models.
  • Table 5 Effect of Standard of Care (SoC) gemcitabine plus cisplatin, or the combination of Example 1 plus SoC, on the growth of a lung patient-derived NSCLC squamous cell carcinoma model Patient-Derived Tumor Model Tumor type Average % change in tumor volume LOF Mutation SoC Example 1 + SoC Day LXFE 937 lung 11 ⁇ 2 -29 ⁇ 25 28 MLL3 (+/-) (2) 788 ⁇ 113 -79 ⁇ 10 46
  • patient derived colorectal tumor CXF 1034 which does not express ARID1A protein and bears mutations in PIK3CA and PTEN, is significantly growth-inhibited when tested with Example 1 with the SoC combination irinotecan hydrochloride trihydrate (formulated in 0.9% NaCl and administered at 20 mpk Q7D IV) plus oxaliplatin (formulated in 5% glucose and administered at 8 mpk Q14D i.p.)
  • Table 6 Effect of Standard of Care (SoC) irinotecan plus oxaliplatin, or the combination of Example 1 plus SoC, on the growth of a patient-derived colorectal carcinoma model.
  • SoC Standard of Care
  • EZH2 inhibitors including but not exclusive to Example 1 or Example 38, alone and/or in combination with Standard of Care (SoC) chemotherapy, in the treatment of ovarian, gastric, lung or colorectal cancers bearing combinations of mutations in components of the SWI/SNF complex and/or MLL complex and/or PI3K pathway.
  • SoC Standard of Care
  • the compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration.
  • Such pharmaceutical compositions and processes for preparing same are well known in the art. See, e.g ., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (D. Troy, et al., eds., 21st ed., Lippincott Williams & Wilkins, 2005 ).
  • Dosages for the SoC compounds in patients may be administered as per the approved dosing or may vary according to the recommendation of a physician.
  • Examples of dosing for the SoC compounds may be, for example, as follows:
  • the doses of carboplatin plus paclitaxel may be 175 mg/m2 IV every 3 weeks of paclitaxel followed by 175 mg/m 2 IV every 3 weeks of carboplatin.
  • the doses of paclitaxel plus oxaliplatin may be 50 mg/m 2 IV weekly of paclitaxel and AUC 2 mg/mL weekly of oxaliplatin.
  • the dosages of gemcitabine plus cisplatin may be 1250 mg/m 2 IV every 3 weeks of gemcitabine plus 75 mg/m 2 IV every 3 weeks of cisplatin.
  • the doses of irinotecan plus oxaliplatin may be 125 mg/m 2 IV weekly or 350 mg/m 2 IV every 3 weeks of irinotecan and 85 mg/m2 IV every 2 weeks of oxaliplatin.
  • the EZH2 compounds of the present invention are generally effective over a wide dosage range.
  • dosages per day may fall within the daily range of up to 5000 mg/day, preferably about 100-2000 mg/day, administered in one or more doses. It will be understood however that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

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Claims (24)

  1. Composé de formule :
    Figure imgb0227
     dans laquelle :
    X représente -CH2-ou-CH2-CH2-;
    Y' représente -NR4R5, -CH(CH3)-cyclohexyl-4-yl-N-méthyl-N-méthoxyéthyle ou -CH(CH3)-cyclohex-4-ylazétidin-1-yle, le radical azétidin-1-yle étant éventuellement substitué par méthoxy, 2-propoxy, méthoxyméthyle, méthoxyéthoxy, cyclopropyloxy, cyclopropylméthoxy, pyrazolyle, méthylpyrazolyle, triazolyle, pyrrolidinyle, tétrahydrofurannyloxy ou morpholinyle;
    R4 représente cyclohex-4-yle substitué par N-méthyl-N-méthoxyéthylamino, N-méthyl-N-cyclopropylamino ou azétidin-1-yle, le radical azétidin-1-yle étant substitué par méthoxy, éthoxy, méthoxyéthoxy, cyclopropyloxy ou pyrazolyle;
    R5 représente méthyle ou éthyle ; et
    R6 représente méthyle ou chloro ; ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Composé ou sel de celui-ci selon la revendication 1, X représentant-CH2-.
  3. Composé ou sel de celui-ci selon la revendication 1, X représentant-CH2-CH2-.
  4. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-3, Y' représentant -CH(CH3)-cyclohexyl-4-yl-N-méthyl-N-méthoxyéthyle ou-CH(CH3)-cyclohex-4-ylazétidin-1-yle, le radical azétidin-1-yle étant éventuellement substitué par méthoxy, 2-propoxy, méthoxyméthyle, méthoxyéthoxy, cyclopropyloxy, cyclopropylméthoxy, pyrazolyle, méthylpyrazolyle, triazolyle, pyrrolidinyle, tétrahydrofurannyloxy ou morpholinyle.
  5. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-4, Y' représentant -CH(CH3)-cyclohex-4-ylazétidin-1-yle, le radical azétidin-1-yle étant éventuellement substitué par méthoxy, 2-propoxy, méthoxyméthyle, méthoxyéthoxy, cyclopropyloxy, cyclopropylméthoxy, pyrazolyle, méthylpyrazolyle, triazolyle, pyrrolidinyle, tétrahydrofurannyloxy ou morpholinyle.
  6. Composé ou sel selon l'une quelconque des revendications 1-5, R6 représentant méthyle.
  7. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-3, Y' représentant -NR4R5.
  8. Composé selon soit la revendication 1, soit la revendication 3, qui est
    Figure imgb0228
     ou un sel pharmaceutiquement acceptable de celui-ci.
  9. Composé selon la revendication 8, qui est la 5-[(4,6-diméthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl]-2-{(1R)-1-[4-(3-méthoxyazétidin-1-yl)cyclohexyl]éthyl}-3-méthyl-5,6,7,8-tétrahydro-4H-thiéno[3,2-c]azépin-4-one ou un sel pharmaceutiquement acceptable de celui-ci.
  10. Composé selon la revendication 9, qui est la 5-[(4,6-diméthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl]-2-{(1R)-1-[trans-4-(3-méthoxyazétidin-1-yl)cyclohexyl]éthyl}-3-méthyl-5,6,7,8-tétrahydro-4H-thiéno[3,2-c]azépin-4-one ou un sel pharmaceutiquement acceptable de celui-ci.
  11. Composition pharmaceutique comprenant le composé ou un sel de celui-ci selon l'une quelconque des revendications 1-10 et un ou plusieurs excipients, supports ou diluants pharmaceutiquement acceptables.
  12. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-10 pour une utilisation thérapeutique.
  13. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-10 pour une utilisation dans le traitement d'un cancer.
  14. Composé ou sel de celui-ci selon la revendication 13, le cancer étant choisi dans le groupe constitué par les lymphomes, les tumeurs rhabdoïdes, les tumeurs qui sont dépourvues de ou déficientes en un ou plusieurs constituants parmi le complexe SWI/SNF, les complexes MLL et la voie PI3K constitutivement active, les sarcomes, un myélome multiple, un mélanome, un cancer gastro-intestinal, un cancer colorectal, un cancer pulmonaire, un cancer rénal, un cancer du sein, un cancer ovarien et un cancer de la prostate.
  15. Composé ou sel de celui-ci pour une utilisation selon la revendication 14, le cancer étant le lymphome diffus à grandes cellules B ou le lymphome folliculaire.
  16. Composé ou sel de celui-ci pour une utilisation soit selon la revendication 14, soit selon la revendication 15, le cancer étant le lymphome diffus à grandes cellules B.
  17. Composé ou sel de celui-ci pour une utilisation selon la revendication 14, le cancer étant une tumeur rhabdoïde dépourvue de SNF5.
  18. Composé ou sel de celui-ci pour une utilisation selon la revendication 14, le cancer étant un cancer gastrique.
  19. Composé ou sel de celui-ci pour une utilisation selon la revendication 14, le cancer étant un cancer ovarien.
  20. Composé ou sel de celui-ci pour une utilisation selon la revendication 14, le cancer étant un myélome multiple.
  21. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-10 pour une utilisation en combinaison simultanée, séparée ou séquentielle avec du carboplatine et du paclitaxel dans le traitement d'un cancer ovarien.
  22. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-10 pour une utilisation en combinaison simultanée, séparée ou séquentielle avec de l'oxaliplatine et du paclitaxel dans le traitement d'un cancer gastrique.
  23. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-10 pour une utilisation en combinaison simultanée, séparée ou séquentielle avec de la gemcitabine et du cisplatine dans le traitement d'un cancer pulmonaire.
  24. Composé ou sel de celui-ci selon l'une quelconque des revendications 1-10 pour une utilisation en combinaison simultanée, séparée ou séquentielle avec de l'irinotécan et de l'oxaliplatine dans le traitement d'un cancer colorectal.
EP16757513.3A 2015-08-27 2016-08-22 Inhibiteurs de l'ezh2 Active EP3341379B1 (fr)

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PL16757513T PL3341379T3 (pl) 2015-08-27 2016-08-22 Inhibitory ezh2
RS20191526A RS59615B1 (sr) 2015-08-27 2016-08-22 Inhibitori ezh2
MEP-2019-322A ME03650B (fr) 2015-08-27 2016-08-22 Inhibiteurs de l'ezh2
SI201630453T SI3341379T1 (sl) 2015-08-27 2016-08-22 Inhibitorji EZH2
HRP20192101TT HRP20192101T1 (hr) 2015-08-27 2019-11-21 Inhibitori ezh2

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EP15382433 2015-08-27
EP15382615 2015-12-11
PCT/US2016/047989 WO2017035060A1 (fr) 2015-08-27 2016-08-22 Inhibiteurs de l'ezh2

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PE20181025A1 (es) 2018-06-27
CR20180104A (es) 2018-04-24
KR20180030704A (ko) 2018-03-23
DOP2018000058A (es) 2018-03-30
AU2016313541A1 (en) 2018-02-15
ECSP18014798A (es) 2018-04-30
CA2994428A1 (fr) 2017-03-02
BR112018003108A2 (pt) 2018-09-25
MX2018002484A (es) 2018-06-15
IL257061A (en) 2018-03-29
RS59615B1 (sr) 2020-01-31
JP6704040B2 (ja) 2020-06-03
CN107922434A (zh) 2018-04-17
DK3341379T3 (da) 2019-12-02
WO2017035060A1 (fr) 2017-03-02
ME03650B (fr) 2020-07-20
PH12018500423A1 (en) 2018-08-29
US9718838B2 (en) 2017-08-01
JP2018530527A (ja) 2018-10-18
HUE047630T2 (hu) 2021-12-28
PL3341379T3 (pl) 2020-05-18
CO2018002033A2 (es) 2018-05-21
ES2756603T3 (es) 2020-04-27
TN2018000058A1 (en) 2019-07-08
CY1122364T1 (el) 2021-01-27
LT3341379T (lt) 2019-12-10
SI3341379T1 (sl) 2019-11-29
TW201718598A (zh) 2017-06-01
US20170066780A1 (en) 2017-03-09
HRP20192101T1 (hr) 2020-02-21
EP3341379A1 (fr) 2018-07-04
MD3341379T2 (ro) 2020-01-31
PT3341379T (pt) 2019-12-16
CN107922434B (zh) 2020-06-19

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